Park Yeoung-Hyun, Son Chul, Seo You-Mi, Lee Yoon Seon, Har Alix, Park Joo-Cheol
Laboratory for the Study of Regenerative Dental Medicine, Department of Oral Histology and Developmental Biology, School of Dentistry, Seoul National University, Seoul, South Korea.
Regenerative Dental Medicine R and D Center, HysensBio Co., Ltd., Seoul, South Korea.
Front Cell Dev Biol. 2021 Apr 26;9:655498. doi: 10.3389/fcell.2021.655498. eCollection 2021.
Dentin, which composes most of the tooth structure, is formed by odontoblasts, long-lived post-mitotic cells maintained throughout the entire life of the tooth. In mature odontoblasts, however, cellular activity is significantly weakened. Therefore, it is important to augment the cellular activity of mature odontoblasts to regenerate physiological dentin; however, no molecule regulating the cellular activity of mature odontoblasts has yet been identified. Here, we suggest that copine-7 (CPNE7) can reactivate the lost functions of mature odontoblasts by inducing autophagy. CPNE7 was observed to elevate the expression of microtubule-associated protein light chain 3-II (LC3-II), an autophagy marker, and autophagosome formation in the pre-odontoblast and mature odontoblast stages of human dental pulp cells. CPNE7-induced autophagy upregulated DSP and DMP-1, odontoblast differentiation and mineralization markers, and augmented dentin formation in mature odontoblasts. Furthermore, CPNE7 also upregulated NESTIN and TAU, which are expressed in the physiological odontoblast process, and stimulated the elongation of the odontoblast process by inducing autophagy. Moreover, lipofuscin, which progressively accumulates in long-lived post-mitotic cells and hinders their proper functions, was observed to be removed in recombinant CPNE7-treated mature odontoblasts. Thus, CPNE7-induced autophagy reactivated the function of mature odontoblasts and promoted the formation of physiological dentin . On the other hand, the well-known autophagy inducer, rapamycin, promoted odontoblast differentiation in pre-odontoblasts but did not properly reactivate the function of mature odontoblasts. These findings provide evidence that CPNE7 functionally reactivates mature odontoblasts and introduce its potential for dentinal loss-targeted clinical applications.
牙本质构成了牙齿的大部分结构，由成牙本质细胞形成，成牙本质细胞是一种长寿命的终末分化细胞，在牙齿的整个生命周期中都能维持。然而，在成熟的成牙本质细胞中，细胞活性显著减弱。因此，增强成熟成牙本质细胞的细胞活性以再生生理性牙本质很重要；然而，尚未发现调节成熟成牙本质细胞细胞活性的分子。在此，我们表明Copine-7（CPNE7）可以通过诱导自噬来重新激活成熟成牙本质细胞丧失的功能。观察到CPNE7在人牙髓细胞的成牙本质细胞前体和成熟成牙本质细胞阶段提高了自噬标志物微管相关蛋白轻链3-II（LC3-II）的表达以及自噬体的形成。CPNE7诱导的自噬上调了牙本质涎磷蛋白（DSP）和牙本质基质蛋白-1（DMP-1），这两种成牙本质细胞分化和矿化标志物，并增强了成熟成牙本质细胞中的牙本质形成。此外，CPNE7还上调了在生理性成牙本质细胞突起中表达的巢蛋白（NESTIN）和微管相关蛋白tau（TAU），并通过诱导自噬刺激成牙本质细胞突起的伸长。此外，观察到在重组CPNE7处理的成熟成牙本质细胞中，脂褐素（一种在长寿命的终末分化细胞中逐渐积累并阻碍其正常功能的物质）被清除。因此，CPNE7诱导的自噬重新激活了成熟成牙本质细胞的功能并促进了生理性牙本质的形成。另一方面，著名的自噬诱导剂雷帕霉素促进了成牙本质细胞前体中的成牙本质细胞分化，但没有适当地重新激活成熟成牙本质细胞的功能。这些发现提供了证据，证明CPNE7在功能上重新激活了成熟成牙本质细胞，并介绍了其在针对牙本质丧失的临床应用中的潜力。
